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The importance of both sex and gender in biological research was highlighted by a report in 2000 from the Institute of Medicine, “Exploring the Biological Contributions to Human Health: Does Sex Matter?”1 This landmark report not only clarified the use of the terms sex (“…a classification, generally as male or female, according to the reproductive organs and functions that derive from the chromosomal complement.”) and gender (“…a person’s self-representation as male or female, or how that person is responded to by social institutions on the basis of the individual’s gender presentation.”) but also addressed the important role that both sex and gender play in health and the development of disease, healthcare delivery, and response to treatment. Furthermore, there were strong recommendations for an increased emphasis on design of studies, so they can be analyzed by sex with adequate power and for a requirement to present the results of studies according to sex in the medical literature. Despite this Institute of Medicine report and the 1993 National Institutes of Health Revitalization Act2,3 that mandated representation of women and men in clinical trials in proportion to the sex-related prevalence of the disease under study, several reports have shown that enrollment of women continues to lag behind their representation among patients with or at risk for cardiovascular disease.4–6 At the same time, increased reporting of the results of clinical trials according to sex leaves the medical community faced with the challenge of interpreting the results of these underpowered subgroup analyses and how to apply them in practice.

In this issue of Circulation: Cardiovascular Interventions, Sotomi et al7 once again raise the challenges of interpreting potential sex-specific responses to therapeutic intervention for cardiovascular disease. However, in doing so, they add the complexity of considering whether sex differences in treatment response, if they exist, may be mediated or modulated by biological (eg, body size, race/ethnicity, and coronary artery diameter) or environmental characteristics (eg, sociocultural, medical practice patterns, and treatment biases) that also vary according to geographic region. In a patient-level analysis of 3 trials of percutaneous coronary intervention (PCI) with drug-eluting stent (DES) versus bypass surgery for left main or multivessel coronary disease (n=3280), for the end point of all-cause mortality, they identified region-specific heterogeneity of the results of subgroup analyses of treatment effect according to sex. In the trials conducted in Asia (BEST [Artery Bypass Surgery and Everolimus-eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease], n=880, and PRECOMBAT [Bypass Surgery versus Angioplasty Using Sirolimus-eluting Stent in Patients with Left Main Coronary Artery Disease], n=600), survival was similar for patients randomized to bypass surgery versus PCI with DES among both women and men. However, in the SYNTAX trial (Synergy between PCI with Taxus and Cardiac Surgery) that enrolled 1800 participants in Europe and the United States, there was significant heterogeneity of treatment effect on all-cause mortality according to sex, with bypass surgery favored over PCI with DES among women (n=402; hazard ratio, 2.21; 99% confidence interval, 1.24–3.94), but no significant difference by revascularization approach among men (n=1398; hazard ratio, 1.01; 99% confidence interval, 0.74–1.36), Pinteraction=0.019.7 Interestingly, in the overview by Sotomi et al, the heterogeneity in the sex × treatment interaction across trials held only for all-cause mortality. Although there was significant heterogeneity of the sex × treatment interaction across trials for the composite of all-cause death, myocardial infarction, or stroke, this was largely driven by the significant heterogeneity for all-cause mortality. For myocardial infarction alone, stroke alone, revascularization, and the composite of major adverse cardiac and cerebrovascular events, results were consistent across trials, and there was no heterogeneity of treatment effect by sex.

Given the consistency of treatment effect by sex for all end points except mortality across the 3 trials, the question remains whether the observed heterogeneity across trials for the end point of all-cause mortality truly reflects region-specific differences in the relationship between sex and treatment effect. It is possible that the differences observed across trials for the sex × treatment interaction on all-cause mortality were simply the play of chance. In SYNTAX, both at the 12-month primary end point and extended 5-year follow-up, all-cause mortality overall was similar between bypass surgery and PCI with DES.8,9 The relevance of a statistically significant sex × treatment interaction is unclear when the overall effect of treatment is neutral. Considering a P value of 0.05, 1 in every 20 subgroup interactions tested would be significant by chance alone. In this light, it is also important to acknowledge that across trials only 24% of participants were women (22.3% in SYNTAX, 23.5% in PRECOMBAT, and 28.5% in BEST); thus, the total number of deaths among women was also small, increasing the likelihood of type I error. Furthermore, even if we assume that the sex × treatment interaction observed in SYNTAX was the truth among European and American women, it should be noted that the confidence intervals around the point estimate for all-cause mortality for the comparison of PCI with DES versus bypass surgery for women in the PRECOMBAT and BEST trials were wide and did not exclude results as extreme as those observed in the subgroup of women in the SYNTAX trial.7 From this perspective, the observations of Sotomi et al7 could reflect the smaller sample sizes of the trials conducted in Asia with limited numbers of deaths for analysis, rather than regional differences in response to treatment by sex.

Baseline clinical characteristics of the populations should also be considered in the discussion of potential differences in results by sex across trials. For example, given the results from the FREEDOM trial (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease),10 showing significantly lower all-cause mortality for bypass surgery than PCI with DES among diabetic patients, differences in rates of diabetes mellitus among men and women in the SYNTAX, PRECOMBAT, and BEST trials may be relevant. Overall, the rate of diabetes mellitus across trials was higher among women than men, but this difference was most extreme in the SYNTAX trial (absolute 9%).7 Differences in trial design (left main only in PRECOMBAT; left main or 3-vessel coronary disease in SYNTAX; 2- or 3-vessel coronary disease in BEST) and procedural approaches (greater use of off pump surgery and left internal mammary grafts in the Asian trials and a greater number of stents placed per patient treated in SYNTAX) also could have contributed to the differences observed between trials.7

Still, as we enter the era of precision medicine, it is intriguing to consider whether unique biological or environmental factors or systematic sociocultural or medical practice differences drive observed responses to treatment of coronary artery disease. With the increasing ability to characterize populations across many axes (eg, clinical, socioeconomic, cultural, and biological), including the use of geospatial information systems to characterize both natural and man-made features of their environment, and the development of novel approaches to integrating this information, we stand to learn much about regional variation in treatment outcomes. Considering how sex and gender influence these complex interactions will be critically important to advancing our understanding of health and successful prevention and treatment of cardiovascular disease. In the meantime, as suggested by Sotomi et al,7 it would seem prudent to validate and calibrate prediction tools developed in 1 population before widespread adoption for use in populations in substantially different practice settings. Even with these efforts, to truly understand the relationship of sex with treatment effect in randomized clinical trials, we must continue to strive to adequately represent women in clinical trials relative to their proportional contribution to the disease under study.

. Geographical difference of the interaction of sex with treatment strategy in patients with multivessel disease and left main disease: a meta-analysis from SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease), and BEST (Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) randomized controlled trials.Circ Cardiovasc Interv. 2017;10:e005027. doi: 10.1161/CIRCINTERVENTIONS.117.005027.